Unit:
Faculty of MedicineLibrary of the School of Health Sciences
Dissertation committee:
Κουλούκουσα Μυρσίνη, Ομότιμη Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Γοργούλης Βασίλειος, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Κοτσίνας Αθανάσιος, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Ευαγγέλου Κωνσταντίνος, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Χαβάκη Σοφία, Αναπληρώτρια Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Λαγοπάτη Νεφέλη, Επίκουρη Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Βάρδας Εμμανουήλ, Επίκουρος Καθηγητής, Τμήμα Οδοντιατρικής, ΕΚΠΑ
Original Title:
Διερεύνηση της ογκογόνου δράσης του παράγοντα αδειοδότησης της αντιγραφής CDC6 στον καρκίνο του προστάτη
Translated title:
Investigation of the oncogenic role of the replication licensing factor CDC6 in prostate cancer
Summary:
Background: Prostate cancer is a hormone-dependent type of cancer that represents a leading cause of cancer morbidity and mortality in men around the world. Androgen deprivation therapy (ADT) remains the mainstay of therapy for patients with prostate cancer, but has proven efficient only in early-stage androgen-responsive disease state. Unfortunately, prostate cancer gradually progresses into an androgen-irresponsive and metastatic disease state for a great number of patients. Based on our previously presented oncogene-induced model for cancer progression, senescence has been established as a very important tumor-barrier mechanism. However, the implication of senescence in the progression of early-stage androgen-dependent to highly aggressive and metastatic castration-resistant prostate cancer (CRPC) should be further investigated.
Materials & Methods: In this study we implemented androgen-responsive (LNCaP) and –irresponsive (C4-2B and PC-3) prostate cancer cells, treated or not with enzalutamide, an Androgen Receptor (AR) inhibitor. In order to identify potential senescence regulators upon treatment with enzalutamide we conducted RNA sequencing and pathway analyses in LNCaP cells to identify. Moreover, we continued with evaluation of the invasive potential of cells and senescence status upon AR signaling inhibition via enzalutamide and/or RNAi-mediated depletion of selected targets in all cell lines, accompanied by bioinformatics analyses on a broad range of in vitro and in vivo datasets. The most important findings were also confirmed in LNCaP and C4-2B mouse xenografts. Assessment of senescence status was performed using the state-of-the-art GL13 staining by immunocytochemical staining and confocal microscopy.
Results: In this study we found that enzalutamide treatment promotes induction of senescence in androgen-dependent cells through downregulation of the replication licensing factor CDC6. Mechanistically, we show that enzalutamide in androgen-dependent cells activates the endogenous levels of GATA2 transcription factor, that functions as a CDC6 repressor, thus resulting in CDC6 downregulation. Intriguingly, in enzalutamide-resistant cells we observed a decrease in GATA2 levels, and a consequent CDC6 stabilization followed by enhanced activation of Epithelial-To-Mesenchymal Transition (EMT) markers and absence of senescence. We demonstrate that CDC6 depletion can converse the oncogenic status and establish senescence irrespective of treatment responsiveness, thereby highlighting the importance of CDC6 for the regulation of prostate cancer progression.
Conclusions: We identify a crucial senescence-mediated GATA2-CDC6 signaling axis which is conversely regulated in enzalutamide-responsive and -irresponsive prostate cancer environments. Upon acquired resistance, GATA2 repression stabilizes CDC6, with harmful consequences in prostate cancer progression through EMT worsening and senescence abrogation. However, bypassing the GATA2-CDC6 axis by experimental silencing of CDC6 is sufficient to reverse oncogenic characteristics and induce senescence, offering a therapeutic window even upon acquiring therapy resistance.
Main subject category:
Health Sciences
Keywords:
Prostate, Cancer
Number of references:
173
File:
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Mourkioti_Ioanna_PhD.pdf
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File access is restricted until 2025-07-25.
